신장이식 환자에서 Rifampin과 Cyclosporine의 약동학적 상호작용

손지홍,윤영란,김경아,박지영,차인준,김양욱,김영훈,신재국,Shon, Ji-Hong,Yoon, Young-Ran,Kim, Kyoung-Ah,Park, Ji-Young,Cha, In-June,Kim, Yang-Wook,Kim, Young-Hoon,Shin, Jae-Gook 대한임상약리학회 2000 臨床藥理學會誌 Vol.8 No.1

Background: We present a case whose plasma cyclosporine concentrations were markedly decreased after adding antituberculosis medications. To assess the effect of rifampin on this pharmacokinetic interaction, we evaluated the pharmacokinetic changes of cyclosporine in kidney-transplanted patients with tuberculosis before and after withdrawing rifampin. Methods : Two separate full pharmacokinetic studies of cyclosporine were performed in four kidney recipients with tuberculosis before and one month after withdrawing rifampin from antituberculosis medications. Multiple blood samples were repeatedly drawn after morning oral dose of cyclosporine, and cyclosporine concentrations were determined by HPLC method. Pharmacokinetic parameters were estimated from noncompartmental method using $WinNonlin{\circledR}$ Results : After withdrawing rifampin, changing patterns of all pharmacokinetic parameters were consistent in all 4 subjects. Corrected Cmax and AUC estimated on the same 100mg dose basis were significantly increased from $291.1{\pm}54.1$ ng/ml to $950.7{\pm}174.7$ ng/ml and from $1483.1{\pm}92.0$ ng/ml ${\cdot}$ h to $6047.2{\pm}666.6$ ng /ml ${\cdot}$ hr, respectively (p<O.Ol). Total oral clearance (Cl/F) estimated during administration of rifampin ($19.8{\pm}3.5$ L/kg) was decreased to $6.0{\pm}0.9$ L/kg after withdrawing rifampin. However, the prolongation of halflife was not statistically significant $(6.1{\pm}1.7 hour vs)$ $10.6{\pm}1.1)$. Conclusions : These results strongly suggest that rifampin markedly decrease the plasma concentration of cyclosporine coadministered through pharmacokinetic interaction, and careful dose readjustment should be considered from frequent monitoring of plasma cyclosporine concentrations in patients taking both cyclosporine and antituberculosis medications including rifampin.

감압병에서 고압산소요법 치료시 NSAID 보조요법의 효과 규명

손지홍 ( Ji-hong Shon ),문중범 ( Joong-bum Moon ),차수강 ( Su-gang Cha ) 국군의무사령부 2005 대한군진의학학술지 Vol.36 No.1

Acetaminophen으로 유발된 간손상에 대한 고압 산소의 치료적 효과에 관한 연구

손지홍 ( Ji-hong Shon ),나희삼 ( Hee-sam Na ),김정욱 ( Jung-wook Kim ),차수강 ( Su-gang Cha ) 국군의무사령부 2004 대한군진의학학술지 Vol.35 No.1

일측 신절제술 후 Netilmicin의 약동학적 특성의 경시적 변화

민권식,손지홍,차인준,정재일,최성협,신재국,윤영란,Min, Kweon-Sik,Shon, Ji-Hong,Cha, In-June,Jung, Jae-Il,Choi, Sung-Hyup,Shin, Jae-Gook,Yoon, Young-Ran 대한임상약리학회 1999 臨床藥理學會誌 Vol.7 No.1

연구배경: 일측 신절제술 후 이를 보상하기 위하여 남은 일측신장은 형태학적, 기능적인 변화를 나타낸다. 본 연구에서는 일측 신절제에 따른 신기능 변화에 따른 약물소실의 변화를 평가하기 위하여 일측 신절제술을 시행한 환자에서 netilmicin의 약동학적 변화를 수술 후 3개월까지 경시적으로 분석하였다. 방 법: 수술 후 netilmicin을 투여 받는 42명 (27명 : 일측 신절제술, 15명 : 대조군, 신절제술이 아닌 비뇨기과적 수술)의 환자를 대상으로, $2.5{\pm}0.3\;mg/kg$의 netilmicin을 일일 2회 반복투여 후 수술 1일 전, 술 후 1일, 3일, 7일 그리고 술 후 3개월에는 1회 투여 수 각각 2회의 채혈을 실시하였다. 이로부터 측정한 혈장 netilmicin 농도를 PCNONLIN을 이용하여 1-compartment 모델에 적용하여 약동학적 파라메터들을 산출하였다. 결 과: 일측 신절제술 후 혈장 크레아티닌치의 증가가 전 연구 기간에 걸쳐 나타났으며, 크레아티닌 청소율은 전 연구 기간 동안에 술전에 비하여 감소된 것으로 나타났다. 한편, 일측 신절제 후 산출된 netilmic의 최고농도는 술전에 비하여 유의한 변화가 없었으나, 술 후 7일 째의 netilmicin 최저 농도는 술전의 값$(0.41{\pm}0.11\;mg/L)$에 비하여 2배 정도 증가하였고 이는 술 후 3개월에는 술전의 수치로 회복되었다. Netilimicin의 혈장 청소율은 수술 후 점차로 감소하여 술 후 7일 째에 술전에 비하여 $27.4{\pm}5.8%$ 감소하여 가장 큰 변화를 보였다. Netilmicin의 반감기는 연장되었으며 신절제 후 7일에 술전에 비하여 $48.7{\pm}9.5%$ 연장되어 가장 큰 변화를 보였다. 변화한 혈장 청소율과 반감기는 술 후 3개월 째에는 술전의 수치로 회복되었다. 일측 신절제 후 감소한 netilmicin의 청소율의 퍼센트 변화량은 혈장 creatinine 값과 유의한 상관관계를 나타내었으며 (r= 0.05, p<0.01), 크레아티닌 청소율과도 유의한 상관관계를 보였다(r=0.47, p<0.01). 결 론: 이상의 결과들은 정상적인 기능을 하고 있는 일측 신장을 절제할 경우 변화된 신기능으로 인해 약물소실이 수개월간 영향을 받을 수 있으므로 일측 신절제술 직후 주로 신장을 통해 배설되는 약물 혹은 활성 대사 물에 대해서는 주의깊게 관찰해야하며, 약동학적 지식을 이용한 개별화된 적정요법을 적용하는 것이 필수적인 것으로 사료된다. Background : After unilateral nephrectomy, one remained kidney adapts morphologically and functionally in order to compensate the loss of opposite kidney. In this study, pharmacokinetics of netilmicin were repeatedly estimated to evaluate the time course of the renal functional changes on drug excretion after unilateral nephrectomy. Methods : After single or multiple doses of netilmicin$(2.5{\pm}0.3\;mg/kg)$, two blood samples were drawn at 1 day before, 1, 3, 7 days and 3 months after operation in 42 subjects (27 patients with unilateral nephrectomy and 15 control patients with general urological operations). Pharmacokinetic parameters were estimated from nonlinear fittings of plasma netilmicin concentrations to one compartment model with using PCNONLIN. Results : The serum creatinine and creatinine clearance were significantly changed compared to those values before operation and to those of control subjects. Without any significant changes of extrapolated peak netilmicin concentrations, trough concentrations increased up to 2.0 folds of baseline level$(0.41{\pm}0.11mg/L)$ at 7days after unilateral nephrectomy. Total netilmicin clearance was gradually decreased and the plasma half-life was prolonged, and the maximum changes of them were observed at 7days after nephrectomy($27.4{\pm}5.8%\;and\;48.7{\pm}9.5%$ of baseline values $90.1{\pm}5.4\;ml/kg/hr$ and $2.6{\pm}0.2hr$, respectively). All these pharmcokinetic changes of netilmicin were recovered to the baseline value at 3 months. The percent changes of netilmicin clearance showed good correlation with the serum creatinine concentration(r=0.50, p<0.01) and creatinine clearance(r=0.47, p<0.01). Conclusions : These results suggest that the renal function on drug excretion seems to change till months later after unilateral nephrectomy of a functional kidney and the close monitoring of a drug and/or metabolite excreted largely by kidney should consider in the subject with very recent unilateral nephrectomy.

Diclofenac Diethylammonium 플라스터제 (류마스탑${\circledR})$의 경피흡수에 따른 임상약동학적 특성의 분석

윤영란,차인준,손지홍,김경아,김민정,박성욱,서승석,최장석,이형기,신재국,Yoon, Young-Ran,Cha, In-June,Shon, Ji-Hong,Kim, Kyoung-Ah,Kim, Min-Jung,Park, Sung-Wook,Seo, Seung-Seok,Choi, Jang-Seok,Lee, Hyeong-Ki,Shin, Jae-Gook 대한임상약리학회 2000 臨床藥理學會誌 Vol.8 No.1

Background: Transdermal absorption pharmacokinetics of diclofenac diethylammonium(DEA) plaster $(Rheumastop{\circledR})$ were estimated after single and multiple application in normal healthy subjects. Methods : Single plaster of 120 mg diclofenac DEA was applied to upper arm of 14 healthy male subjects for 24 hours and replaced with new plaster every 24 hours for following 14 days. Serial blood samples were drawn after the first dose and the last dose of the plaster and intermittent blood samples were drawn at 3, 5, 7 and 10 days of the study. Diclofenac concentrations in plasma, urine and plaster were determined by high performance liquid chromatography method. Pharmacokinetic parameters were estimated by both noncompartmental analysis and compartmental analysis of 2-compartment, 2-segment simultaneous input model with using $(NONMEM{\circledR})$ Results : The amount of diclofenac absorbed during 24 hour application of each diclofenac DEA plaster was estimated to $6.6{\pm}3.5$ mg and was corresponded to 6.9 % of total amount of diclofenac measured in the in tact plaster(average 95.17 mg). After the first dose of a diclofenac plaster, the average peak plasma concentration was reached to maximum concentration $(7.4{\pm}3.6 ng/ml)$ at $12.4{\pm}9.2$ hour. After multiple doses of diclofenac DEA plaster, the plasma concentration reached to peak level $(15.9{\pm}11.7 ng/ml)$ at $7.9{\pm}7.4$ hours, then concentrations were declined very slowly to $(10.0{\pm}5.1 ng/ml)$ at the time of next application. The mean AUC of diclofenac at steady state was estimated to $273{\pm}205 ng/ml$ h. From the compartmental model for the transdermal absorption of diclofenac DEA plaster, $75{\pm}14$ % of diclofenac dose was described by the burst zero order input model and the remained was by slow first order input model. The estimated volume of distribution (Vd/F) was estimated to $2.2{\pm}0.8$ L/kg and half life was $3.4{\pm}0.8$ hour. Conclusions : The diclofenac DEA plaster which shows initial burst and slow continuous input absorption kinetics appears to be able to maintain constant plasma level during 24 hour application. The measured plasma concentration-time profiles at steady-state are expected to be adequate for therapeutic effect, taking into account the comparable results to those from twice a day application of 185 mg diclofenac HEP plaster of which clinical effect has been well established. However, further clinical trials in patients are remained to document the clinical effects of this new diclofenac plaster.

황백의 주요 구성 화합물에 의한 약물대사효소 및 약물수송단백 저해능 평가

구혜영,김현미,손지홍,유광현,Ku, Hei-Young,Kim, Hyunmi,Shon, Ji-Hong,Liu, Kwang-Hyeon 한국해양바이오학회 2006 한국해양바이오학회지 Vol.1 No.3

본 연구는 황백에 함유되어 있는 주요 화합물인 berberine, palmatine, limonin 및 rutaecarpine의 CYP2D6 및 p-glycoprotein 활성에 대한 저해정도를 탐색함으로써, 황백을 다른 양약과 병용시 약물상호작용을 유발할 수 있는 가능성을 평가하고자 하였다. 인체 간 마이크로좀 시료에 CYP2D6 동효소의 기질약물인 dextromethorphan과 NADPH 재생성계 및 저해제 ($200{\mu}M$)를 첨가한 후 반응시켜 생성된 대사물을 LC/MS/MS를 이용하여 정량하여 CYP2D6 동효소 활성의 변화를 평가하였다. 또한 약물수송단백인 p-glycoprotein의 활성은 L-MDR1 세포주를 이용한 calcein AM 축적 실험을 통하여 평가하였다. 그 결과 식물 알카로이드인 berberine에서 강력한 CYP2D6 활성 저해능을 관찰하였으며, 저해 효과는 농도 의존적으로 증가하였으며, mechanism-based 저해 기전을 나타내었다. 그러나 limonine과 rutaecarpine은 CYP2D6 저해 활성을 보이지 않았고, p-glycoprotein 기능에 대해서는 평가한 어떤 화합물도 저해 활성을 나타내지 않았다. 황백의 주요 성분인 berberine의 CYP2D6 활성 저해능을 고려할 때, 황백을 CYP2D6 기질약제와 병용시 약물상호작용을 유발할 가능성을 보여준다. 이러한 황백의 CYP2D6를 매개로한 임상적인 약물상호작용 가능성은 임상시험을 통하여 추가적인 검정이 필요할 것으로 사료된다. We evaluated the potential of major components of Phellodendri cortex to inhibit the activities of CYP2D6 and p-glycoprotein. The abilities of berberine, palmatine, limonin, and rutaecarpine to inhibit CYP2D6-mediated dextromethorphan O-demethylation and calcein AM accumulation were tested using human liver microsomes and L-MDR1 cell, respectively. Berberine strongly inhibited CYP2D6 isoform activity, whereas limonin and reuaecarpine did not. The $IC_{50}$ value of berberine was reduced after preincubation with microsomes in the presence of NADPH generating system, suggesting that berberine is a mechanism based inhibitor. In addition, all chemicals tested, didn't show inhibitory effect on p-glycoprotein activity. These results suggest that berberine has potential to inhibit CYP2D6 activity in vitro. Therefore, in vivo studies investigating the interactions between berberine and CYP2D6 substrates are necessary to determine whether inhibition of CYP2D6 activity by berberine is clinically relevant.

Ketoprofen 전신투여후 활액내로의 분포 약동학 : 집단약동학적 분석

박지영,손정환,윤영란,손지홍,차인준,서승석,최장석,신재국,Park, Ji-Young,Sohn, Jeong-Hwan,Yoon, Young-Ran,Shon, Ji-Hong,Cha, In-June,Seo, Seung-Suk,Choi, Jang-Suk,Shin, Jae-Gook 대한임상약리학회 2001 臨床藥理學會誌 Vol.9 No.1

Background : The disposition kinetics of ketoprofen into synovial fluid was estimated to predict the time course of ketoprofen concentration in synovial fluid in patients with arthritis. Methods : After repeated oral doses of ketoprofen 100 mg twice daily, ketoprofen concentrations of plasma and synovial fluid were determined at steady-state by high performance liquid chromatography(HPLC) in 17 arthritic patients. Plasma pharmacokinetic parameters were estimated from one compartmental open model and the penetration pharmacokinetic parameters into synovial fluid were estimated from nonlinear fitting to the effect compartment model using $NONMEM^{\circledR}$. Results: At steady-state, the observed peak concentrations of plasma and synovial fluid were $4.6{\pm}3.2{\mu}g/ml\;and\;2.4{\pm}1.9{\mu}g/ml$ at 2 hours and 5 hours after the last dose, respectively. Plots of plasma ketoprofen concentration against synovial concentration showed anticlockwise hysteresis, suggesting the time delay in the distribution of ketoprofen into synovial fluid from plasma. The estimated average rate constant for the ketoprofen loss from synovial $fluid({\kappa}_{co})$ was $0.16\;h^{-1}$. From the simulation of ketoprofen concentration curves, the predicted $C_{max}$ of synovial fluid was corresponded to 76.6 % of the plasma $concentration(1.44\;{\mu}g/ml\;vs\;1.881{\mu}g/ml)$ and time lag of $T_{max}$ between both fluid spaces was estimated to 3.1 hours. Conclusions : These results suggest that the time course of ketoprofen concentration in synovial fluid is different from plasma concentration-time profile after systemic administration of ketoprofen. The effect compartment model approach appears to be useful to predict the kinetics of ketoprofen in synovial fluid from the plasma data.

고압 환경에서 발생하는 폐 산소독성에 관한 연구 : 위험 인자

나희삼 ( Hee Sam Na ),손지홍 ( Ji Hong Shon ),차수강 ( Su Gang Cha ) 국군의무사령부 2003 대한군진의학학술지 Vol.34 No.1

한국인의 Cytochrome P450 2C19 유전형 분석

윤영란,이준호,김문경,손지홍,이상섭,김종신,이순용,차인준,신재국,Yoon, Young-Ran,Lee, Jun-Ho,Kim, Moon-Kyung,Shon, Ji-Hong,Lee, Sang-Seop,Kim, Jong-Shin,Lee, Soon-Yong,Cha, In-June,Shin, Jae-Gook 대한임상약리학회 2002 臨床藥理學會誌 Vol.10 No.1

배경 : 간 cytochrome P450 2C19 (CYP2C19) 효소군은 유전적 다형성을 나타내는 대표적인 약물대사효소의 하나로, 본 연구에서는 다수의 한국인에서 CYP2C19 유전자 변이를 분석하고, 이들 변이 allele들의 출현빈도를 타 종족에서의 결과와 비교 분석하였다. 방법 : 282 명의 건강한 한국인 피험자에서 CYP2C19 (*2와 *3) allele 변이를 polymerase chain reaction restriction fragment length polymorphism (PCR­RFLP) 방법을 이용하여 분석하였다. 결 과 : 282명의 한국인 피험자 CYP2C19*1/*1 (41.8%), CYP2C19*1/*2 (35.5%), 및 CYP2C19*1/*3 (8.5%) allele 변이를 가지는 extensive metabolizer(EM)는 총 242명으로 나타났다. 40명 (14.2%)은 CYP2C19 의 poor metabolizer(PM)로 밝혀졌는데, 이들의 allele 빈도는 CYP2C19*2/*2, CYP2C19&2/*3, 및 CYP2C19*3/*3 가 각각 8.9%, 3.9%, 1.4% 로 나타 났다. 또한, 총 564개 allele에서 각 allele의 출현빈도는 CYP2C19*1, CYP2C19*2, 및 CYP2C19*3가 각각 63.8%, 28.6% 및 7.6%로 나타났다. 결 론 : 한국인의 CYP2C19 PM 유전형의 빈도는 중국인, 일본인 등의 동아시아인보다 다소 낮았으나, 이는 서양인에 비해서는 유의하게 높은 것으로 나타났다. Background : The cytochrome P450 2C19 (CYP2C19) is a well known microsomal oxidizing enzyme showing genetic polymorphism. We extensively evaluated the frequency distribution of the CYP2C19 allelic variants in a Korean population and compared to those of other ethnics. Methods : Genotyping of CYP2C19 (*2 and *3) was carried out in a total of 282 unrelated Korean subjects. CYP2C19 genotypes were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results : Two hundred forty two of 282 Korean subjects, carried extensive metabolizer(EM) genotypes including CYP2C19*1/*1 (41.8%), CYP2C19*1/*2 (35.5%), and CYP2C19*1/*3 (8.5%), respectively. Forty subjects (14.2%) were identified to have CYP2C19 poor metabolizer(PM) genotype, and the frequencies of CYP2C19*2/*2, CYP2C19&2/*3, and CYP2C19*3/*3 were 8.9%, 3.9%, 1.4% respectively. The allele frequencies of CYP2C19*1, CYP2C19*2, and CYP2C19*3 among 564 alleles evaluated were 63.8%, 28.6% and 7.6%, respectively. Conclusions : These results suggest that frequency of CYP2C19 PM genotypes is slightly lower than that of other East Asians including Chinese and Japanese, but significantly higher than Caucasian.

적정약물요법을 위한 약동학/약력학적 개념

손지홍,신재국 大韓臨床藥理學會 2000 臨床藥理學會誌 Vol.8 No.1